Leptin is an adipocyte-derived hormone that signals the status of body energy stores to the hypothalamus by binding and activating a specific "long" isoform of the leptin receptor (LRb) that is highly expressed in a subset of hypothalamic neurons. In this manner, adequate leptin levels signal energy repletion and serve to repress appetite and permit energy-expensive neuroendocrine functions, such as high metabolic rate, reproduction, and growth. While the genomics of LRb-expressing neurons are of great interest for the understanding of leptin-regulated physiology and for the identification of potential therapeutic targets, only a small percentage of hypothalamic neurons express LRb and are leptin-sensitive. Thus, the anatomic and/or functional dissection of LRb-expressing cells within the mixed population of hypothalamic neurons for genomic analysis is problematic. This proposal outlines a novel approach for isolating mRNA in a cell-type specific manner and development of a cellular model of leptin responsiveness. This will enable the identification of genes expressed only in LRb-expressing cells and the analysis of genes subject to hormonal and\or nutrient regulation in these cells. Through this process we will be able to generate a list of potential therapeutic targets for treatment of obesity and other neuroendocrine disorders.